Most of the bacteria in the small intestine are Gram-positive, while those in the colon are mostly Gram-negative. The first part of the colon is mostly responsible for fermenting carbohydrates, while the latter part mostly breaks down proteins and amino acids. Bacterial growth is rapid in the cecum and ascending colon, which has a low pH, and correspondingly slow in the descending colon, which has an almost neutral pH. The body maintains the proper balance and locations of species by altering pH, the activity of the immune system, and peristalsis.
Gastritis is an inflammation of the lining of the stomach. There are many possible causes. Gastritis may be caused by excessive alcohol consumption, or the prolonged use of nonsteroidal anti-inflammatory drugs, also known as NSAIDs, such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic injury, burns, or severe infections. Certain diseases, such as pernicious anemia and chronic bile reflux, or autoimmune disorders, can cause gastritis as well. Importantly, gastritis may be caused by infection with bacteria, such as Helicobacter pylori. The most common symptom is abdominal upset or pain. Other symptoms are indigestion, abdominal bloating, nausea, and vomiting, or a feeling of fullness or burning in the upper abdomen.
Gastroenteritis is inflammation of the gastrointestinal tract, involving both the stomach and the small intestine, often resulting in acute diarrhea. The inflammation is caused most often by infection with certain viruses, but may also be caused by bacteria or parasites. Worldwide, inadequate treatment of gastroenteritis kills 5 to 8 million people per year, and is a leading cause of death among infants and children under 5. Similarly, enteritis refers to inflammation of the small intestine with similar causes.
Many different bacteria can cause gastroenteritis, including Salmonella, Shigella, Staphylococcus, Campylobacter jejuni, Clostridium, Escherichia coli, Yersinia, and others. Some sources of the infection are improperly prepared food, reheated meat dishes, seafood, dairy, and bakery products. Each organism causes slightly different symptoms but all result in diarrhea. Colitis, inflammation of the large intestine, may also be present.
Several Salmonella species are capable of causing gastroenteritis, including S. enterica, which is subdivided into several serovars. Illustrative examples include Serovar Typhi (previously known as S. Typhi), which is the disease agent responsible for typhoid fever, and Serovar Typhimurium (also known as S. Typhimurium), which leads to a form of human gastroenteritis sometimes referred to as salmonellosis. Several Shigella species are also responsible for gastroenteritis. Illustrative examples include S. boydii; S. dysenteriae, which is a major cause of dysentery; S. flexneri; and S. sonnei. An illustrative species of Campylobacter causing gastroenteritis in humans is C. jejuni. It is one of the most common causes of human gastroenteritis in the world. Yersinia species are also a cause of gastroenteritis, an illustrative example is the zoonotic Y. enterocolitica. The disease caused by Y. enterocolitica is called yersiniosis. Some strains of Helicobacter are pathogenic to humans and are strongly associated with peptic ulcers, chronic gastritis, duodenitis, and stomach cancer. An illustrative species responsible for disease in humans is H. pylori. 
Reportedly clarithromycin (CLR) is the only known macrolide antibiotic that works in vivo on Helicobacter pylori. Although other macrolide antibiotics show in vitro activity against H. pylori, there often are not sufficiently active at low pH to work in vivo. In addition, may antibiotics, such as azithromycin (AZI) and telithromycin (TEL), do not achieve sufficiently high tissue and blood circulating levels to show efficacy on H. pylori. Without being bound by theory, it is suggested herein that high protein binding may prevent other macrolide antibiotics from having such in vivo activity. Ordinarily, a minimum pH is required for macrolide antibiotics to show activity.
It has been surprisingly discovered herein that triazole-containing macrolides, including ketolides, exhibit high anti-bacterial activity at low pH, or at pH levels much lower than the minimum pH required by other macrolide antibiotics for efficacy. It has also been unexpectedly discovered herein that the compounds described herein have high anti-bacterial activity against gastroenteritis disease pathogens (GDP), such as H. pylori (HP), and gastritis and diarrheal illness pathogens, such as Camplylobacter jejuni (CJ), Salmonella spp. (SAL) and Shigella spp. (SHI).
In one illustrative embodiment, compounds of Formula (I) are described herein
including pharmaceutically acceptable salts, hydrates, solvates, esters, and prodrugs thereof.
In one aspect, R10 is hydrogen or acyl. In another aspect, X is H; and Y is OR7; where R7 is a monosaccharide or disaccharide, alkyl, aryl, heteroaryl, acyl, or C(O)NR8R9, where R8 and R9 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y are taken together with the attached carbon to form carbonyl.
In another aspect, V is C(O), C(═NR11), CH(NR12, R13), or N(R14)CH2, where N(R14) is attached to the C-10 carbon of the compounds of Formulae 1 and 2; wherein R11 is hydroxy or alkoxy, R12 and R13 are each independently selected from the group consisting of hydrogen, hydroxy, akyl, arylalkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R14 is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl.
In another aspect, W is H, F, Cl, Br, I, or OH.
In another aspect, A is CH2, C(O), C(O)O, C(O)NH, S(O)2, S(O)2NH, C(O)NHS(O)2. In another aspect, B is (CH2)n where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons. In another aspect, C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureido, or carbamoyl.
In another embodiment, compositions including a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein. The pharmaceutical compositions may include additional pharmaceutically acceptable carriers, diluents, and/or excipients.
In another embodiment, methods are described herein for treating diseases arising from pathogenic organism populations causing enteritis, gastroenteritis, and/or a related disease. The methods include the step of administering a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein, to a patient in need of relief or suffering from a disease caused by a pathogenic organism.
In another embodiment, uses are described herein for the manufacture of medicaments. The medicaments include a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein, or one or more compositions thereof described herein. The medicaments are suitable for treating diseases, such as enteritis, gastroenteritis, and/or a related disease arising from pathogenic organism populations.
In another embodiment, compounds, compositions, methods, and medicaments are described herein for treating diseases caused by H. pylori. 
Each embodiment of the compositions, methods, and medicaments include a therapeutically effective amount of one or more triazole-containing macrolides or ketolides, such as one or more compounds or formula (I). The therapeutically effective amount is administered to a patient in need of relief or suffering from the disease.
In another embodiment, compounds, compositions, methods, and medicaments are described herein for treating diseases caused by H. pylori. that include the co-administration of one or more proton pump inhibitors, such as but not limited to omeprazole, esopremazole, and the like.
In another embodiment, oral formulations of the compounds and compositions described herein include enteric coating. Without being bound by theory, it is believed herein that enteric coating may prevent stomach acid degradation of proton pump inhibitors to achiral intermediates.
In another embodiment, compounds, compositions, methods, and medicaments are described herein for treating enteritis, gastroenteritis, and related diseases, that include the co-administration of other antibiotics, including but not limited to fluoroquinolone antibiotics, metronidazoles, vancomycin, and the like, and combinations thereof.
In another embodiment, compounds, compositions, methods, and medicaments are described herein for treating enteritis, gastroenteritis, and related diseases, accompanied by diarrhea symptoms, that include the co-administration of other compounds for decreasing gut motility. It is appreciated that the macrolide compounds described herein may also decrease gut motility. Illustrative gut motility decreasing agents include but are not limited to loperamide, an opioid analogue commonly used for symptomatic treatment of diarrhea, and bismuth subsalicylate (BSS), an insoluble complex of trivalent bismuth and salicylate.